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MEH > 7.1 - Anaemia > Flashcards

7.1 - Anaemia Flashcards

1
Q

what is anaemia

A

a haemoglobin concentration lower than the normal range

note that normal range will vary with age, sex and ethnicity

anaemia in itself is not a dignosis, but a manifestation of an underlying disease state - important to establish the cause of the anaemia

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2
Q

signs and symptoms of anaemia

A

haemoglobin carries O2 to the tissues, so the general signs and symptoms are related to this and these are not particularly specific; could easily be something else

syptoms
* shortness of breath
* palpitations
* headaches
* claudication - pains in the legs + arms when using
* angina
* weakness and lethargy
* confusion

signs
* pallor
* tachycardia (heart trying to increase cardiac output to compensate)
* systolic flow murmur
* tachypnoea - rapid breathing
* hypotension

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3
Q

what is koilonychia

A

spoon shaped nails
associated with iron deficiency anaemia

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4
Q

what is angular stomatitis

A

inflammation of the corners of the mouth
indicates iron deficiency anaemia

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5
Q

what is glossitis

A

inflammation and depapillation (ie tongue is smooth) of tongue
associated with vit B12 deficiency

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6
Q

what type of anaemia is associated with abnormal facial development

A

thalassaemia
(due to expansion of haemopoetic tissues)
rare in recent times as preventable with early diagnosis

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7
Q

why might anaemia develop

some of these are in more detail on seperate cards

A

during development in bone marrow
- reduced or dysfunctional erythropoiesis (ie not making enough RBCs)
- abnormal haem synthesis
- abnormal globin chain synthesis

peripheral red blood cells
- abnormal structure eg sickle cell
- mechanical damage (ie mechanical heart valve can physically crunch RBC)
- abnormal metabolism (RBC at risk as they don’t have nucleus so can’t increase enzyme output)

removal/exit
- increased removal by RES (for reasons above, any faulty RBC is removed by RES)
- excessive bleeding (eg stabbing or bleeding caused by NSAIDS etc)

note: anaemia is often multifactorial - eg myelofibrosis and thalassemia

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8
Q

what does erythropoietin (EPO) do?

A
  • has a role in the hormonal control of erythropoiesis
  • ie low blood oxygen → pericytes in kidney sense hypoxia and produce EPO → EPO travels in bloodstream → EPO binds to receptors on erythroblasts in bone marrow → stimulates red cell production → increased number of red cells in blood, and therefore higher blood oxygen
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9
Q

how does anaemia develop: reduced or dysfunctional erythropoiesis

A
  • lack of response in haemostatic loop of EPO eg in kidney disease, kidney stops making EPO
  • marrow unable to respond to EPO eg after chemo, toxic insult or parovirus
  • cancer or myelofibrosis ie marrow infiltrated by cancer (or fibrous tissue, myelofibrosis), the number of normal haemopoietic cells is reduced
  • anaemia of chronic disease iron is not made availble to marrow for RBC production
  • myelodysplastic syndrome where abnormal clones of marrow stem cells limit the capacity to make blood cells
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10
Q

why might anaemia develop: defects in haemoglobin synthesis

A

haemoglobin has 4 haem groups per molecule, each containing Fe2+, and has 4 globin chains (2 α and 2 β chains)

  • mutations in genes encoding globin chain proteins so can’t synthesise haemoglobin effectively eg α thalassaemia, β thalassaemia, sickle cell disease
  • defects in haem synthetic pathway can lead to sideroblastic anaemia
  • insufficient iron to make haem groups
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11
Q

why might anaemia develop: abnormal structure and mechanical damage

A

… results in haemolytic anaemai

inherited
* mutations in genes coding for proteins involved in interactions between plasma membrane and cytoskeleton
* causes proteins to be left out
* cells can become less flexible and damaged
* break up in circulation or removed more quickly by RES
* eg hereditary spherocytosis

aquired damage
* more likely to be reversible
* causes microangiopathic haemolytic anaemia
* deformation of cells caused by shear stress and cells pass through defective heart valve
* cells snagging on fibrin strands in small vessels where increased activation of clotting cascade has occured
* heat damage from severe burns (causes dehydration, water leaves cell, damage to shape)
* osmotic damage (eg drowing in freshwater) can cause water to enter cells and cause haemolysis

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12
Q

what are schistocytes

A
  • blood cell fragments results from mechanical damage
  • eg caused by aquired damage
  • presence of schistocytes suggest that some form of pathology is present
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13
Q

why might anaemia develop: defects in red cell metabolism

A

two examples: defects in cell metabolism more likely in RBCs as they don’t have nucleus to increase enzyme output

G6PDH deficiency
- decreased amount of glucose 6-phosphate dehydrogenase activity
- lower amounts of NADPH
- means that lower amounts of GSH are produced
- lower GSH means less protection from oxidative stress
- oxidative stress occurs: eg infection, drugs
- this can cause lipid peroxidation (cell membrane damage and membrane less flexible) or protein damage (causes aggregates of cross-linked haemoglobin, aka heinz bodies)
- can avoid specific triggers, so easier to manage

pyruvate kinase deficiency
- PK is final enzyme in glycolysis
- caused by rare genetic defects
- red blood cells lack mitochondria so only source of energy is through glycolysis
- defective glycolysis pathway
- RBCs to rapidly become deficient in ATP
- undergo haemolysis

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14
Q

why might anaemia develop: excessive bleeding

A

due to acute blood loss eg injury, surgery, childbirth or chronic bleeding

chronic bleeding
* heavy periods
* repeated nosebleeds
* haemorrhoids
* occult GI bleeding (blood lost in stool) eg ulcers, diverticulosis, polyps, intestinal cancer
* kidney or bladder tumours (blood lost in urine)
* chronic NSAID usage…

chronic NSAID usage
- eg ibuprofen, aspirin or naproxen
- commonly used for treatment with pain and inflammation
- induce GI injury/bleeding by…

inhibition of cyclooxygenase (COX) activity → platelets don’t work as they should

direct cytotoxic effects on epithelium

occult = no obvious signs or symptoms

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15
Q

why might anaemia develop: reticuloendothelial system (RES)

A
  • in haemolytic anaemias, red cells are destroyed more quickly as they are abnormal or damaged
  • damage can occur within the blood vessels (intravascular haemolysis) or within the RES (extravascular haemolysis)
  • in autoimmune haemolytic anaemias, autoantibodies bind to the red cell membrane proteins → recognised by macrophages in spleen → destroyed
  • splenomegaly often occurs with haemolytic anaemias as the spleen is doing extra work
  • macrophages in spleen and other RES tissues remove damaged or defective red cells
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16
Q

what are the two key features to help work out cause of anaemia

A

RBC size
is it macrocytic, microcytic, normocytic?

the presence or absence of reticulocytosis
ie has the bone marrow responded normally?

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17
Q

what are the two key features to help work out cause of anaemia

A

RBC size
is it macrocytic, microcytic, normocytic?

the presence or absence of reticulocytosis
ie has the bone marrow responded normally?

18
Q

what are reticulocytes

and when should reticulocytes hopefully be higher than normal?

A
  • immature red blood cells
  • ie those that have just been released from bone marrow into the blood
  • no nucleus
  • take one day to mature into erythrocytes
  • slightly larger than mature RBCs so an increase in reticulocytes will bring up the MCV
  • reticulocyte count very useful in evaluating anaemia
  • shows if marrow is capable of responding to anaemia
  • ie want a high reticulocyte count in anaemic patients as it shows that the bone marrow is compensating and trying to recover
19
Q

anaemia evaluation

A

is there an increase in the reticulocyte count?
* yes: bone marrow is functioning normally → is there evidence of haemolysis
* no: problem in the bone marrow → what are the RBC indices

is there evidence of haemolysis ie high bilirubin and high LDH
* yes: cause may be autoimmune, MAHA, haemoglobinopathies, enzyme defects, membrane defects
* no: look for evidence of bleeding, eg acute blood loss, chronic bleeding, spleen sequestration

what are the RBC indicies
* microcytic: thalassaemia, anaemia of chronic disease, iron deficiency, lead poisioning, sideroblastic anaemia
* macrocytic: vit B12 deficiency, folate deficiency, myelodysplasia, liver disease, alcohol toxicity
* normocytic: primary or secondary bone marrow faliure

20
Q

what are the different macrocytic anaemias

details on sep cards

A
  • megaloblastic anaemias are most common
  • macronormoblastic erythropoiesis are generally due to acquired causes
  • stress erythropoiesis are conditions associated with a high reticulocyte count

these are all anaemias where the red cell size is bigger than normal

21
Q

megaloblastic anaemias

and some example causes

A
  • type of macrocytic anaemia, where MCV is greater than normal
  • interference with DNA synthesis during erythropoiesis causes development of nucleus and cytoplasm to be dysynchronised
  • development of nucleus is retarded in relation to cytoplasm
  • cell division delayed and erythroblast is stuck in G1 growth phase
  • erythroblasts continue to grow, forming megaloblasts which give rise to larger red blood cells

examples
- vit B12 / folate deficiency
- drugs that interfere with DNA synthesis (eg some anti-cancer drugs)
- some erythroid leukaemias where DNA synthesis is retarded

22
Q

macronormalblastic erythropoiesis

and some examples

A
  • type of macrocytic anaemia
  • normal relationship between development of nucleus and cytoplasm is retained
  • erythroblasts are larger than normal and give rise to larger red cells
  • generally due to acquired causes

examples
- liver disease
- alcohol toxicity
- some myelodysplastic syndromes

23
Q

stress erythropoiesis

A
  • type of macrocytic anaemia
  • conditions associated with high reticulocyte count
  • reticulocytes are overall bigger, so bring up the overall MCV
  • high levels of erythropoietin leads to an expanded and accelerated erythropoiesis

examples
- recovery from blood loss due to haemorrhage
- recovery form haemolytic anaemia

24
Q

what is folate

A
  • synthetic form = folic acid
  • synthesised in bacteria and plants
  • present in wide variety of animal and plant sources
  • high in green leafy veg and in liver
  • absorbtion mainly from duodenum and jejunum (GI conditions will affect this)
  • converted to tetrahydrofolate (FH4) by intestinal cells
  • metabolic role to provide carbons for other reactions
  • recipient reactions include synthesis of nucleotide bases required for DNA and RNA synthesis

note: B12 and folate feed into same metabolic point

25
Q

symptoms of folate deficiency

A
  • those related to anaemia
  • reduced sense of taste
  • diarrhoea
  • numbness and tingling in feet and hands
  • msucle weakness
  • depression
26
Q

causes of folate deficiency

A
  • dietary deficiency ie poor diet
  • increased requirements (pregnancy, increased erythropoiesis, severe skin disease)
  • disease of the duodenum and jejunum (eg coeliac diease, chron’s)
  • drugs which inhibit dihydrofolate reductase (eg methotrexate)
  • alcoholism (poor diet and damage to intestinal cells)
  • urinary loss of folate in liver disease and heart faliure
27
Q

why do pregnant women need to have lots of folate

A
  • folic acid (μg/day) taken before conception and during first 12 weeks of pregnacy
  • prevents majority of neural tube defects in babies
  • eg spina bifida
  • folic acid is added to things like flour in the USA, but not in UK
28
Q

vitamin B12

A
  • water soluble vitamin
  • largest and most structurally complex of all the vitamins
  • essential co-factors for DNA synthesis (due to it’s role in folate metabolism)
  • required for normal erythropoiesis
  • essential for normal function and development of CNS
  • produced by bacteria, not plants
  • largely obtained by animal sources eg meat, fish, milk, eggs, cheese, marmite
  • essential that people on vegan diet eat foods fortified with B12 or take B12 supplment (10μg daily)
29
Q

vitamin B12 absorbtion

A
  • B12 released from food proteins by proteolysis in stomach
  • B12 then binds to haptocorrin
  • haptocorrin B12 complex digested by pancreatic proteases in small intestine
  • this releases B12 which then binds to intrinsic factor
  • intrinsic factor produced by gastric parietal cells
  • intrinsic factor-B12 complex binds to cubam receptor, which mediates uptake of complex by receptor-mediated endocytosis into enterocytes
  • after lysosomal release into enterocytes, B12 exits via MDR1
  • binds to transcobalamin in blood and transported around bloodstream
  • majority of B12 is stored in liver (stores last 3-6 years)
30
Q

vitamin B12 deficiency causes

A

common
- dietary deficiency (eg vegan)
- lack of intrinsic factor = pernicious anaemia (on diff card)
- diseases of ileum (eg chron’s, ileal resection etc)

less common
- lack of transcobalamin (congenital defect)
- chemical inactivation of B12 (eg using too much nitric oxide gas)
- parasitic infestation can trap B12
- some drugs can chelate intrinsic factor

31
Q

what is pernicious anaemia

A
  • decreased or absent intrinsic factor (IF)
  • causes progressive exhaustation of B12 reserves
  • autoimmune disease
  • 2 types of antibody (Ab)…
    → blocking Ab blocks binding of B12 to IF
    → binding Ab prevents receptor mediated endocytosis

fairly common type of B12 deficiency

32
Q

what is pernicious anaemia

A
  • decreased or absent intrinsic factor (IF)
  • causes progressive exhaustation of B12 reserves
  • autoimmune disease
  • 2 types of antibody (Ab)…
    → blocking Ab blocks binding of B12 to IF
    → binding Ab prevents receptor mediated endocytosis

fairly common type of B12 deficiency

33
Q

symptoms of vit B12 deficiency

A
  • any of those related to anaemia and also…
  • glossitis and mouth ulcers
  • diarrhoea
  • paraesthesia (numbness and tingling in hands, arms, legs and feet)
  • disturbed vision (due to B12 role in CNS)
  • irritability
34
Q

subacute combined degeneration of the cord

A

B12/folate deficiency can also affect the nervous system
→ folate deficiency in pregnancy can cause neural tube defects
→ B12 deficiency associated with focal demyelination

  • B12 deficiency more often results in reversibe peripheral neuropathy
  • however, can also result in serious condition: subacute combined degeneration of the cord
  • this involves degeneration of the posterior and lateral columns of the spinal cord
  • more likely irreversable
  • symptoms involved: gradual onset weakness, numbness and tingling in arms, legs and trunk that gets progressively worse, along with changes in mental state

often, neurological symptoms present before anaemia, so always seek urgent advice from haematologist if neurological involvement is suspected in a patient with B12 deficiency

35
Q

the B12/folate link

A
  • the methionine cycle (uses vit B12) and the folate cycle (that uses dietary folate / folic acid) work side-by-side
  • the methionine cycle is important for production of things like adrenaline, creatine and melatonin from precursors
  • the folate cycle is important for synthesis of thymidine, which is essential for DNA synthesis
  • lack of B12 will ‘trap’ folate in the stable methyltetrahydrofolate form
  • this prevents its use in other reactions (eg in the folate cycle, for DNA synthesis)
36
Q

why do B12 and folate deficiency cayse a megaloblastic anaemia

A
  • both folate and B12 deficiency ultimately result in thymine deficiency
  • to keep cell production going in absence of thymidine, uracil (RNA) is incorporated instead
  • DNA repair enzymes detect these errors and constantly repair by excision
  • results in asynchronous maturation between nucleus and cytoplasm
    → nucleus doesn’t fully mature
    → cytoplasm matures at the normal rate
  • vitamin B12 and folate are both necessary for nuclear division and maturation
  • when these are deficient, nuclear maturation and cell divisions lag behind cytoplasm development
  • leads to large red cell precursors with inappropriately large nuclei and open chromatin
  • the mature cells are also large, leading to macrocytic anaemia
37
Q

what is anisopoikilocytosis

A

fancy word for ‘variance in size and shape’ of blood cells

38
Q

megaloblastic features in blood film

A
  • anisopoikilocytosis: variance in size and shape
  • tear drop red cells
  • ovalocytes
  • hypersegmented neutrophils (6 or more lobes in nuclei) - only really seen in B12 deficiency
  • macrocytic cells (ie larger than normal)
39
Q

why is LDH raised in megaloblastic anaemia

A

LDH = plasma lactate dehydrogenase

raised due to increased cell destruction and increased cell production

40
Q

treatment of vitamin B12 and folate deficiency

A

folate deficiency = oral folic acid
vitamin B12 = oral cyanocobalamine. For pernicious anaemia = hydroxycobalamine intramuscular ★ for life

  • be aware of hypokalaemia at beginning of treating severe pernicious anaemia. THis is due to increased K+ requirement as erythropoiesis increases back to its normal rate
  • be aware of blood transfusion in patients with severe anemia caused by B12 deficiency → can cause high output cardiac faliure, so be extremely cautious

★ not oral = this is because these patients can’t absorb it as they have no intrinsic factor present

MEH (19 decks)

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